The respiratory apparatus is the generic term for organs and tissues related to respiration, and it plays important roles in life support such as the intake of atmospheric oxygen and the excretion of carbon dioxide generated as a result of metabolism.
Representative respiratory diseases with the cough include, for example, lung cancer, carcinomatous lymphopathy, rib fracture, spontaneous pneumothorax, cold syndrome (upper respiratory infection), pulmonary tuberculosis, interstitial pneumonitis, pleurisy, pneumonia, acute bronchitis, chronic bronchitis, pulmonary emphysema, pneumoconiosis, bronchiectasis, diffuse panbronchiolitis, bronchial asthma, pulmonary embolism, and pulmonary infarction.
Cough is occurred as follows. The lungs enlarge as a result of deep inspiration, and the pressure in the lungs increases due to strong contraction of the respiratory muscles. The muscles of larynx suddenly relax, and thereby the air is rapidly exhaled with secreted materials to the respiratory tract. When secreted materials or foreign substances accumulate on the mucous membranes of the respiratory tract and/or there are abnormalities in the pleura, lungs, or diaphragma, their impulses stimulate the cough center in the posterolateral medulla oblongata and causes the attack of coughing (“Saishin Yakurigaku (in Japanese, Modern Pharmacology)”, 10.3 Antitussive Agent, Sumiko Fujino, 1990, Kodansha Ltd.).
Cough is mainly caused by excessive secretion from the mucous membranes of respiratory tract, by chemical stimuli such as smoke and gas, by foreign substances, by inflammation of respiratory tract, by allergic reactions, by the compression of bronchi by tumor in the thoracic cavity, or by psychogenic factors. The worsening and chronicity of cough consumes energy of the respiratory muscles and physical strength to thereby prevent recovery of the underlying disease.
Antitussive agents are classified as centrally-acting antitussive agents which block the cough center and peripherally-acting antitussive agents which reduce the stimuli to peripheral receptors. The centrally-acting antitussive agents typified by codeine phosphate generally are very effective but induce adverse actions such as respiratory depression, constipation, nausea, emesis, headache, sleepiness, and eruption. The repeated use of them also induces tolerance and/or addiction. The peripherally-acting antitussive agents typified by methylephedrine exhibit only mild antitussive actions. Recently, the opioid delta (δ) receptor antagonists have been developed as antitussive agents. However, because the δ receptor is deeply involved in mental and emotional behaviors, these antagonists should induce adverse actions (Nat. Genet. 25, 2, 195, 2000). Accordingly, demands have been made on antitussive agents having higher efficacy and less adverse actions.
Huegi et al. have reported 4-hydroxypiperidine derivatives showing analgesic actions (J. Med. Chem. 26, 42, 1983). These compounds, however, are morphine-like centrally-acting analgesic agents having affinity for opiate receptors and differ in structure from the compounds of the present invention. PCT International Publication No. WO 00/61557 has disclosed 4-hydroxypiperidine derivatives having antiarrhythmic actions. In addition, PCT International Publication No. WO 00/61558 has disclosed 4-hydroxypiperidine derivatives which are useful as agents for treating neuropathic pain. These compounds act upon sodium channels and selectively prevent persistent sodium currents more than transient sodium currents. However, these compounds differ in structure from the compounds of the present invention.
Japanese Patent Application Laid-open No. Sho 60-163861 has disclosed 4-(phenoxymethyl)piperidin-4-ol derivatives containing aryloxymethylpiperidinol derivatives having antidepressive, antiarrhythmic or antihypertensive actions. However, it has lacked the disclosure about antitussive actions. These compounds also differ in structure from the compounds of the present invention. PCT International Publication No. WO 93/02052 has disclosed 2-(4-hydroxypiperidino)-1-alkanol derivatives as anti-ischemic agents. However, it has lacked the disclosure about antitussive actions. These compounds differ in basic structure from the compounds of the present invention.
Piperidine derivatives having antitussive actions have been disclosed as nociceptin receptor agonists in PCT international publication No. WO00/06545 but they have different structures from those of the compounds of the present invention.
PCT International Publication No. WO 00/06544 has described cyclic amine derivatives (piperidine derivatives) with the tachykinin-antagonistic action. These derivatives can be useful for the treatment of asthma, cough, or pain related to tachykinin. These derivatives, however, are different in structure from the compounds of the present invention which have specific substituents.
PCT International Publication No. WO 02/22572 has disclosed 3-substituted azetidine derivatives, 3-substituted pyrrolidine derivatives or 3-substituted piperidine derivatives. They have a modulating actions on dopamine, serotonin or norepinephrine receptors, or their transporters. These derivatives are useful for the treatment of anxiety, depression, erectile dysfunction, Alzheimer disease, mental disorder, urinary incontinence, and/or neuropathic pain. The publication, however, has lacked the disclosure about antitussive actions.
Drugs to be developed must be required to have not only high pharmacological activities but also high safety over long time. They also must achieve the rigid criteria in, for example, absorption, distribution, metabolism, and secretion. They must satisfy various requirements in, for example, drug interaction, desensitization or tolerance, gastrointestinal absorption, transition rate, absorption rate and first pass effect, organ barrier, protein binding, the induction of drug metabolic enzymes, excretion route and clearance, and application method (application site, method, and object). It is very difficult to satisfy these requirements. Thus, new drugs must have a wider safety range and more excellent pharmacokinetic properties.
These general requirements in the development of drugs are applied to agents for treating respiratory diseases. In addition, the agents for treating respiratory diseases typified by antitussive agents must have less adverse actions and higher efficacy than conventional equivalents such as the conventional centrally-acting antitussive agents, peripherally-acting antitussive agents, and the δ opioid receptor antagonists.